Covalent Modification of the Mycobacterium tuberculosis FAS-II Dehydratase by Isoxyl and Thiacetazone

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• 作者：Anna E. Grzegorzewicz ; Nathalie Eynard ; Annaïk Quémard ; E. Jeffrey North ; Alyssa Margolis ; Jared J. Lindenberger ; Victoria Jones ; Jana Korduláková ; Patrick J. Brennan ; Richard E. Lee ; Donald R. Ronning ; Michael R. McNeil ; Mary Jackson
• 刊名：ACS Infectious Diseases
• 出版年：2015
• 出版时间：February 13, 2015
• 年：2015
• 卷：1
• 期：2
• 页码：91-97
• 全文大小：451K
• ISSN：2373-8227

文摘

Isoxyl (ISO) and thiacetazone (TAC) are two antitubercular prodrugs formerly used in the clinical treatment of tuberculosis. Although both prodrugs have recently been shown to kill Mycobacterium tuberculosis through the inhibition of the dehydration step of the type II fatty acid synthase pathway, their detailed mechanism of inhibition, the precise number of enzymes involved in their activation, and the nature of their activated forms remained unknown. This paper demonstrates that both ISO and TAC specifically and covalently react with a cysteine residue (Cys61) of the HadA subunit of the dehydratase, thereby inhibiting HadAB activity. The results unveil for the first time the nature of the active forms of ISO and TAC and explain the basis for the structure–activity relationship of and resistance to these thiourea prodrugs. The results further indicate that the flavin-containing monooxygenase EthA is most likely the only enzyme required for the activation of ISO and TAC in mycobacteria.